Somatic Evolution in Non-neoplastic IBD-Affected Colon.
Adult
Aged
Aged, 80 and over
Aging
/ genetics
Clonal Evolution
/ genetics
Colitis
/ genetics
Colitis, Ulcerative
/ genetics
Crohn Disease
/ genetics
DNA-Binding Proteins
/ genetics
Epithelial Cells
/ metabolism
F-Box-WD Repeat-Containing Protein 7
/ genetics
Female
Humans
INDEL Mutation
Inflammatory Bowel Diseases
/ genetics
Interleukin-17
/ metabolism
Intestinal Mucosa
/ metabolism
Male
Middle Aged
Mutation Rate
Phylogeny
Point Mutation
Receptors, Cell Surface
/ genetics
Ribonucleases
/ genetics
Toll-Like Receptors
/ genetics
Transcription Factors
/ genetics
Whole Genome Sequencing
Crohn's disease
IL17
PIGR
ZC3H12A
inflammatory bowel disease
intestinal epithelia
mutation rate
mutational signatures
somatic mutations
ulcerative colitis
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
08
03
2020
revised:
01
05
2020
accepted:
24
06
2020
pubmed:
23
7
2020
medline:
30
3
2021
entrez:
23
7
2020
Statut:
ppublish
Résumé
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
Identifiants
pubmed: 32697969
pii: S0092-8674(20)30813-8
doi: 10.1016/j.cell.2020.06.036
pmc: PMC7427325
pii:
doi:
Substances chimiques
ARID1A protein, human
0
DNA-Binding Proteins
0
F-Box-WD Repeat-Containing Protein 7
0
FBXW7 protein, human
0
Interleukin-17
0
OSCAR protein, human
0
Receptors, Cell Surface
0
Toll-Like Receptors
0
Transcription Factors
0
Ribonucleases
EC 3.1.-
ZC3H12A protein, human
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
672-684.e11Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests C.A.A. is a paid consultant for Genomics plc and Bristol-Myers Squibb. All other authors declare no competing interests.
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